Project 4:The overall goal of this project remains to study the interactions between autonomic and metabolic mechanisms involved in cardiovascular regulation. In this funding period we propose to determine the role of the autonomic nervous system in the cardiovascular and metabolic abnormalities associated with obesity and the metabolic syndrome. It is postulated that obesity leads to a compensatory increase in sympathetic activity intended to increase energy expenditure and lipolysis. Indeed, muscle sympathetic nerve activity, a direct measurement of baroreflex-modulated sympathetic outflow, is positively correlated to body weight and visceral fat. We propose, however, that sympathetic activation not only fails to improve the metabolic abnormalities associated with obesity, but it is detrimental and contributes to cardiovascular and metabolic complications. We have previously shown that autonomic withdrawal with the ganglionic blocker trimethaphan can be used to reveal human forms of sympathetically-dependent and -independent hypertension. Our preliminary data using this paradigm suggest that the autonomic nervous system is the primary determinant of the increase in blood pressure associated with obesity, but contributes little, if any, to increasing resting energy expenditure or lipolysis. We have also observed an increase in markers of inflammation (CRP) and oxidative stress (F2-isoprostanes) in obesity and other conditions characterized by sympathetic activation, and, conversely, a decrease in these markers in patients with low sympathetic function. Based on these preliminary observations, we hypothesize that the increased sympathetic activity present in obesity contributes to hypertension, impaired lipolysis, insulin resistance, and inflammation/oxidative stress associated with this disorder. To test this hypothesis we propose to compare the effects of acute and chronic sympathoinhibition, in lean and obese patients with hypertension, and in normal controls. Proving that the sympathetic activation associated with obesity does not result in compensatory beneficial metabolic effects, but is detrimental because it contributes to the cardiovascular and inflammatory/oxidatie stress abnormalities associated with this condition, may lead to a more effective treatment.